1. Field of the Invention
This invention relates to formulations of gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays.
2. Reported Developments
In the delivery of certain slightly water-insoluble drugs intended to act by contact with the mucosal surface of the gastrointestinal tract (hereinafter sometimes referred to as GI tract) without substantial absorbance therethrough into the blood stream, the problem of insufficient adherence and dvelve time are often encountered. Drug, such as antacids, antimicrobial and antifungal agents tend to pass through the GI tract rapidly without providing sufficient local preventive/unactive effects.
Accordingly, there is a need to provide oral GI formulations that are safe, efficacious and have sufficient dvell or contact time with the GI mucosa. Such formulations should have excellent mucosal coating properties for both the upper and lower GI tract, i.e. it should have mucoadhesive or bioadhesive properties that enable the entire GI tract to be coated. Since the slightly watersoluble drugs do not by themselves possess such bioadhesive or mucoadhesive properties, the formulations containing them must provide the same.
The identification of surface active stabilizers with bioadhesive or mucoadhesive properties that enable coating of the entire GI tract with therapeutic agents has not been reported to date.
Bioadhesion is usually achieved by interaction of either a synthetic or natural polymeric substance with the mucosal membranes of the GI tract. Such technology has been employed to enhance drug delivery by decreasing the transit time of a drug substance in the GI tract and hence promote an opportunity for enhanced absorption. With regards to the development water-insoluble or poorly water-soluble drug formulations intended to coat the GI tract, it is important to identify mucosal adhesives that coat the GI surfaces and affect diseased or abnormal tissues. Highly charged carboxylated polyanions are good candidates for use as bioadhesives in the GI tract. See, for example: Park, K. and Robinson, J. R., Bioadhesion: Polymers and Platforms for Oral-Controlled Drug Delivery; Method to Study Bioadhesion. Int. J. Pharm., 19, 107 (1984). The formation of a bioadhesive bond between a polymeric substance and the mucosal lining of the GI tract can be visualized as a two step process, i.e., initial contact between the two surfaces and the formation of secondary bonds due to non-covalent interactions. Bioadhesives specific for the GI tract must interact with the mucus layer during attachment. Mucus, a general term for the heterogenous secretion found on the epithelial surfaces of the GI tract, is made of the following components: glycoprotein macromolecules, inorganic salts, proteins, lipids and mucopolysaccharides. These glycoproteins typically consist of a protein core with carbohydrate side chains. This forms a network of mucus that is a continuous layer covering the GI tract. From a bioadhesive perspective, mucus consists of highly hydrated, crosslinked linear, flexible yet random coiled glycoprotein molecules with a net negative charge. Understanding the principles of bioadhesion is the basis for formulating an oral compositions for coating the GI tract. Bioadhesion accounts for the interaction between a biological surface and a biomaterial substance. As noted previously, bioadhesive agents are usually polymeric substances that adhere to tissues by ionic or covalent bonds or by physical attachment. Several theories of bioadhesion have been published including electronic, adsorption, wetting, diffusion and fracture theories. Bioadhesives bind to membrane surfaces and are retained for variable periods of time.
We have now discovered that certain therapeutic drugs in a combination with bioadhesive or mucoadhesive surfactants and pharmaceutically acceptable clays provide excellent coating on the GI tract for a prolonged period of time so that the therapeutic drugs are able to affect diseased conditions which may be present in the GI tract.
In accordance with the present invention, there is provided an orally/rectally administrable GI formulations containing an effective amount of a water-insoluble or poorly water-soluble therapeutic agent. There is further provided a method for affecting diseased conditions in the Gi tract comprising oral or rectal administration to a patient an effective amount of the above-identified formulation to prevent or cure such diseased conditions.